Anti-inflammatory steroid solutions



United States Patent .880.130 ANTIIJNFLAMMATORY STEROID SOLUTIONS Ri h rH- J hnscn, Kalamazoo, Mich, .assignor to The Upi hn p y,- K am oo. Mih, a o p t on 9f Mifi gan No Drawing. Application December ,24, 1956Serial No. 630,013

invention relates to novel compositions of matter and a novel process.for the preparation of the same, and is particularly directed to thepreparation of chemically and physically stable,- clear aqueoussolutions of anti-inflammatory steroid hormones of :the11)3,'l.7a,21-.-ttihydroxypregnane-3,ZO-dione. class, such ashydrocortisone, 2-rnethylenehydrocortisone, Li -hydrocortisone,6-methylhydrocortisone, .6-methyl-A -hydrocortisone, 16-hydroxy-9a-fluoroh-ydrocortisone, 16-hydroxy-9a-fluoro-A -hydrocortisone, andthe 21-esters and the 1,6,21 diesters thereof which solutions areadapted for topical application to sensitive tissues such as the tissuesof the eye, ear, nose, and throat.

Compositions according to the invention having the desired clarity,stability, and adaptability for topical application to sensitive tissuesare obtained by dissolving the steroid hormone in a vehicle consistingessentially of water and as a solubilizing agent a nonionic surfactantobtained by condensing sorbitan monooleate and ethylene oxide. Thesurfactant shall be referred to hereinafter as polyoxyethylene sorbitanmonooleate. Using polyoxyethylene sorbitan monooleate, i.e., "Tween 80as the solubilizing agent in a concentration of about two to about 25percent of the vehicle, it is possible to obtain chemically and physicalstable, clear solutions of the steroid hormone in concentrationssubstantially greater than the max um s bil ty of th hormone in water atnormal temperature. For example, with a vehicle consisting essentiallyof one cubic centimeter of water and 1.00 milligrams of Tween 80, it ispossible to obtain clear, stable solutions containing as much as twomilligrams of hydroonc p r cub c centim ter, whereas the maximumsolubility of hydrocortisone without the surfactant is 0.28 milligramper cubic centimeter.

The novel solutions of this invention are uniquely characterized bythe'fact that they can be safely applied to sensitive tissues such asthose of the eye, ear, nose, and throat without causing irritation, andby the fact that they contain sufficiently high concentration ofdissolved steroid hormone to bring about effective antiinflammatoryaction when applied to such tissues. Heretofore, it has not beenpossible to obtain clear, chemically, and physically stable solutions ofanti-inflammatory steroid hormones which are not irritating to sensitivetissues such as those of, the eye, ear, nose, and throat and at the sametime contain sufficient quantity of the hormone for effectiveanti-inflammatory action. The novel compositions of the invention,therefore, provide an entirely new type of medicament and make possiblean entirely new yp of ea ment f r inflam d tissues f he ey ear. nose,and throat. While laims have been made of such compositions and such anew type of treatment, it is significant that heretofore no productmaking possible this new type of treatment has been offered to themedical profession. Thus, while it has been proposed to solubilizehydrocortisone with other types of solubilizing agents, the solutions soformed have not been suitable for oph thalmic purposes.

2,880,130 Patented Mar, 31, 1959 Different procedures have been foundeifective for making up solutions according to the invention. Accordingto one procedure, the nonionic surfactant is dissolved in water, and thesteroid hormone is stirred in the resulting solution at room temperatureuntil the desired solution is obtained. Thereafter any adjuvants, suchas salts, where isotonic solutions are wanted, preservatives, andbuffers, are added. Also, other water-soluble drugs may then be added.It is not necessary, however, that the ingredients be added in thissequence. They can be added all at once for example. Advantageously, thenonionic surfactant is dissolved in a portion'of the required water, sayfrom about fifty to ninety percent of that required, and the steroidhormone and other soluble ingredients are dissolved in the resultingsolution. The balance of the water required in the formulation is thenadded. This procedure provides for more facile control of the finalconcentration and is made possible by the fact that when less than thefull quantity of water is used, the concentration of the nonionicsurfactant is proportionally higher, and the dissolving power of thesolution is proportionally greater.

The second procedure, which has been found advantageous, is to heat thesolution containing the steroid hormone in order to facilitate thesolution of the steroid hormone and/or to stabiliie'the solution. It hasbeen found that by heating the solution between about forty degreescentigrade and the decomposition point, a more stable solution isobtained. Advantageously the heating can be carried out in an autoclaveat a temperature of about degrees centigrade in order to obtainsimultaneously both stabilization and sterilization. It has also beenfound that approximately twice as much steroid hormone can be dissolvedif the solution is heated. Thus, two entirely different and distinctefiects are obtained by the heating, namely, (1) it is possible therebyto make more concentrated solutions, and (2) it is possible to obtainmore stable solutions. It appears, therefore, that some kind of complexis formed between the nonionic surfactant and the steroid hormone whichis stabilized by heating. In any event, substantially more stablesolutions are obtained on heating over a considerable period. Effectivestabilization has been obtained on heating for sixty minutes at seventyto eighty degrees centigrade. Generally speaking satisfactory resultscan be obtained by heating from fifteen minutes to ninety minutes ormore depending on the temperature. A shorter time, however, cansometimes be used and'any greater practical time can be used.

The above procedures can be utilized for preparing chemically andphysically clear, aqueous solutions of any anti-inflammatory steriodhormone of the l'1B,l7a,2l-trihydroxypregnane-3,20-dione class. Thiscomprises hydrocortisone and the anti-inflammatory analogs thereof.Since the solutions of the invention are intended for application tosensitive tissues such as those of the eye, ear, nose, and throat, it isdesirable to avoid using an antiinflammatory steroid hormone which hashigh mineral corticoid activity. Such anti-inflammatory steroidhormones, therefore, as hydrocortisone, Z-methylenehydrocortisone, ti-hydrocortisone, 6-methylhydrocortisone, 6- methyll -hydrocortisone,16-hydroxy 9a fluorohydrocorstisone, and 16-hydroxy-9a-fluoro-A-hydrocortisone are preferred. 2-methylenehydrocortisone can be usedadvantageously where systemic activity is not desired. Unless otherwisespecified, the free alcohols and the therapeutically active estersthereof are included. For example, the 21-esters and the 16,21-diestersof acetic acid, propionic acid, tertiarybutylacetic acid, diethylaceticacid, acrylic acid, mono, di-, and trichloracetic acid, succinic acid,tricarballylic acid, glutaric acid, 3,3-dimethyl glutaric, acid,aconitic acid, itaconic acid, and like aliphatic monosteroid hormones,such as A -hydrocortisone and particularly with 6-methyl-A-hydrocortisone, 16-hydroxy-9 afiuorohydrocortisone,l6-hydroxy-9a-fluoro-A -hydrocortisone, the various 2l-esters and16,21-diesters can be used 'advan'tageously because satisfactorily highconcentrations of the anti-inflammatory steroid hormone can be obtainedwithin the permissible limits on the amount of the nonionic surfaceactive agent that can be used satisfactorily. The amount of nonionicsurfactant can be varied, but, in view of the purpose for which thecompositions are intended, namely, for topical application to sensitivetissues, such as tissues of the eye, ear, nose, and throat, it isdesirable that the concentration shall not exceed about 25 percent.Entirely satisfactory solutions are obtained with solutions containingten percent of these surfactants, with and without the application ofheat. Thus, stable solutions containing as much as 0.2 percent(percentage is' by weight unless otherwise specified) hydrocortisone.have been obtained with ten percent aqueous solutions of Tween 80. til; lower concentrations of the nonior'ric surfactant 'give clear,'stablesolutions when the heating procedure is followed, as more particularlyshown in Example 1. Still lower concentrations of nonionic surfactantcan be used, especially where it is not necessary as in the. case of themore active anti-inflammatory steroid hormone, such as the 6-methyl-A-hydrocortisone, to have such a high concentration in the solution. Ingeneral, therefore, the concentration of nonionic surfactant in theformulations according to this invention can range from about two toabout 25 percent.

Compositions according to the invention, therefore, can have thefollowing general formulations:

Percent Anti-inflammatory steroid hormone 2nx Nonionic'surfactant 2-25Preservative Up to 1.5 Solution salts (including buffer salt if any)- Upto 2.0 Lactose Up to 25 Other drugs Up to 30 Water 100 wherein 1:represents the solubility of the anti-inflammatory steroid hormone inwater at room temperature in percent and n is from one to ten. Lactoseis added when it is desired to lyophilize the preparations and functionsas a bulking agent. The other drugs used are generally antibacterialagents, water-soluble antibiotics and sulfa drugs for example.

, The following examples are illustrative of the processes and productsof this invention and are not to be construed as limiting.

EXAMPLE 1 Sterile aqueous solution of hydrocortisone (0.2%)

Formulation:

Tween 80 grams 100 -Hydrocortisone do 2.1 Sodium citrate ..do 2.0 Sodiumchloride do 3.7 Chlorobutanol do.. 5.5

- Water for injection, q.s. ad. 1 liter.

PROCEDURE A .Dissolve in about 860 cubic centimeters of water forinjection (room temperature) in the above order allowing each to.dissolve before the next ingredient is added. Add

With the more active anti-inflammatory I PROCEDURE B Dissolve the Tweenin 800 cc. of water for injection by stirring and heating to sixtydegrees centigrade. Crush any large lumps in the hydrocortisone, add tothe Tween 80 solution and dissolve with stirring and heating at sixty toseventy degrees centigrade for one hour. Cool the solution to 25 degreescentigrade and add the sodium chloride and chlorobutanol. When thechlorobutanol is completely in solution (slow agitation), then dissolvethe the sodium citrate andadd, water for injection to adjust to thefinal volume of one liter. Sterilize the solution by filtration througha sterile filter pro-washed with five percent sodium bicarbonatesolution followed by distilled water.

Procedure B has an'advantage over procedure Ain that solutions whichcontain approximately two times the concentration of hydrocortisone canbe obtained. The eflfect of heat on the solubilityofhydrocortisone isshown in the following table: i

TABLE 1 Approximate Maximum solubility, mgJcc.

Concentration of Tween 80 Procedure Procedure A (without 13 (with heat)heat) Procedure B also hasthe advantage that the stability of thesolutions is substantially greater.

EXAMPLE 2 Sterile aqueous solution, hydrocortisone 0.2 percent neomycinsulfate 0.6 percent Using the formulation and procedures of Example 1with the following formulation:

Tween 80 grams Water for injection, q.s. ad. 1 liter.

clear, stable solutions containing 0.2 percentlhyglrocortisone and 0.6percent neomycin sulfate in a neutral isotonic vehicle were obtained.Procedure A was satisfactoryfor hydrocortisone lot 1; procedure B forother lots of hydrocortisone.

In place of or in addition to the neomycin sulfate there can besubstituted other water-soluble antibiotics such as tetracycline andoxyand chlor-tetracycline hydrochlorides, sodium penicillin (G, O, V andlike forms), polymyxin (B y and other forms) sulfate, streptomycinsulfate, erythromycin hydrochloride, bacitracin, gramicidin, andnovobiocin, or a combination of two or more of the same. The followingexamples are illustrative.

1 EXAMPLE 3 Sterile aqueous solution, hydrocortisone 0.2 percent,polymyxin B sulfate 12,000 units/cc.

milligrams of hydrocortisone and 12,000 units of polymyxin B sulfate percubic centimeter.

EXAMPLE 4 Using the formulation and procedures of Example 2 except thattwo grams of polymyxin B sulfate (6,000 units/mg.) was added along withthe neomycin sulfate, there was obtained clear, stable solutionscontaining two milligrams of hydrocortisone, twelve milligrams ofneomycin sulfate, and 12,000 units of polymyxin B sulfate per cc.

In place of hydrocortisone in the above formulations, there can besubstituted other anti-inflammatory steroid hormones of the l1B,170,21-trihydroxypregnane-3,20- dione class. Preferably those having lowmineral corticoid activity such as hydrocortisone,Z-methylenehydrocortisone, n -hydrocortisone, 6-methylhydrocortisone and6-methyl-A -hydrocortisone, 16?hydroxy-9a-fluorohydrocortisone,16rhydroxy-9c-fluormA -hydro,cortisone, and the esters thereof as setforth above. The following examples are illustrative.

EXAMPLE 5 Sterile aqueous solution of A ehydrocortisone (0.2%)

Formulation:

Tween 80 V gr ams 100.0 N-hydrocor-tisone r pdo 2.1 Sodium chloride do4.7 Chlorobutanol do... 5.5 Sodium citrate ,,u -do 2.0 Water forinjection, q.s. ad, 1 liter.

PROCEDURE Dissolve the Tween 80 in 833 cubic centimeters of water forinjection by stirring while heating to approxi mately 65 degreescentigrade. Add the A -hydrocor-tisone and dissolve by stirring andheating at seventy to eighty degrees centigrade for one hour. Cool thesolution to room temperature. Then dissolve the sodium chloride andchlorobutanol making sure the solution is complete. Then dissolve thesodium citrate and adjust volume with water for injection to one liter.Pass the solution through a sterile filter, pre-washed with five percentsodium bicarbonate solution and water for injection.

1 E AMP E 6 Sterile aqueous solution of A -hydrocortisone (0.1%)Formulation:

Tween 80 ,grams 100 Delta hydrocortisone do 1.05 Sodium chloride do 3.7Chlorobutanol do 5.5 Sodium citrate do 2.0 Water for injection, q.s. ad.1 liter.

PROCEDURE Dissolve the Tween 80 in 400 cubic centimeters of water forinjection. Then add and dissolve the A -hydrocortisone. Add 458 cubiccentimeters of water for injection and dissolve the sodium chloride andchlorobutanol. Finally dissolve the sodium citrate and adjust to oneliter with water for injection. Pass the solution through a sterilefilter, pre-washed with five percent sodium bicarbonate solution andwater.

With the lower concentration of A -hydrocortisone it is not necessary touse heat to obtain a clear, stable solution.

EXAMPLE 7 Sterile aqueous solution containing N-hydrooortisone (0.1%)and neomycin sulfate (0.6%) and bacitracin (500 u/cc.) and polymyxz'n(5,000 u/cc.) and a soluble powder for preparing the same Using theprocedure of Example 6 with the following formulations:

Tween g am .50 -h-yd iso e ur c-ac... 1.5 N ycin su ate .6.- ly nyx n sfate (110,000 un'tsma) do 0-6 Ba ac n (5.0 units g.) qaaa-f- -w- 2Lactose V V I p a d v250 Sodium citrate dn 3.0

Water for injection, liter. i

there are obtained (a) a clear, stable solution containing one milligramof A -hydrocortisone, 6.5 milligrams of neomycin, 600 units ofbacitraci-n and 6,000 units of polymyxin B sulfate per cubic cen imeterand (b) a water-soluble product from which said solution can bereconstituted. This water-soluble product is obtained by apportioningthe solution in five cubic centimeter portions into vials andlyop'hilizing the solution in the vials.

Each vial then contains 250 milligrams Tween 80, 5.25 milligrams A''hydrocortisone, 32.5 milligrams neom-ycin sulfate, fifteen milligramssodium citrate, 1250 milligrams of lactose, 30,000 units of polymyxin Bsulfate and 3,000 units of bacitracin.

In the lyophilized preparations the amount of nonionic surfactant shouldnot exceed about, five percent, since too much surfactant results in anonredispersible cake.

EXAMPLE 8 Sterile aqueous solution containing A -hydmcortisone (0.1%)and neomycin sulfate (0.6%)

Water for injection, V Adi liter. 0

there is obtained a clear, stable, neutral solution containing onemilligram of n -hydrocortisone and 6.5 milligrams of neomycin sulfateper cubic centimeter.

EXAMPLE 9 Sterile aqueous solution containing N-hydrocortisone and i cinand olubl Powder for preparing the same Using the formulation andprocedures of Example 7 except that twenty grams. of bacitracin (fiftyunits per mg.) is used in place of the three antibiotics, there areobtained (a) a clear, neutral solution (limited stability due to thebacitracin') containing 1 mg. of A hydrocortisone and 1,000 units of.bacitracin per cubic centimeter in an isotonic vehicle and (Ir) solublepowder from which said solution can be reconstituted.

Using the same formulations, except for the antibiotic, and the sameprocedure, soluble reconstitutable powders can be prepared with otherantibiotics, such as sodium penicillin and polymyxin B sulfate, whichhave limited stability in aqueous solutions.

In place of the chlorobutanol, other preservatives can be used toprevent bacteria and fungal contamination of the solutions. Other suchsuitable preservatives include benzyl alcohol, myristyl gamma picoliniumchloride, phenyl mercuric nitrate, benzalkonium chloride, phenylethylalcohol, p-chlorophenyl-a-glycerol ether, methyl and propyl parabens,thimerosal. Also the buffer salt (sodium citrate) can be omittedprovided it is replaced with sufficient other salt to maintainisotonicity. The solutions can contain also other water-soluble drugssuch as phenylephrine hydrochloride, sodium sulfacetamide,chlorprophenpyridamine gluconate, thonzylamine hydrochloride, sodiumpropionate, and the like.

The hydrocortisone and n -hydrocortisone in the above examples can bereplaced by G-methyl-hydrocortisone (6-methyl-11B,17a,21-trihydroxy-4-prcgnene-3,20-dione), 6- methyl-Ahydrocortisone (6 methyl 1lfi,17a,21 trihydroxy-l,4pregnadiene-3,ZO-dione), l6-hydroxy-9a-flu-orohydrocortisone l 113,16a,171:,21-tetrahydroxy-9u-fluoro-4- pregnene-3,20-dione), and16-hydroxy-9a-fluoro-A -hydrocortisone (11,8,16ot,17a,21 tetrahydroxy 9afluoro-l,4- pregnadiene-3,20-dione), and the 21 esters thereof to givemore potent formulations because of the higher antiinfiamrnatoryactivity of these steroids. -Alternatively the amount of these steroidscan be reduced to give formulations of equivalent potency.Z-methylene-hydrocortisone (2methylene-l118,170:,2l-trihydroxy-4-pregene-3, 20-dione) can be usedwhere an anti-inflammatory steroid hormone having topical but littlesystemic activity is desired.

It is to be understood that the invention is not to be limited to theexact details of. operation or exact compounds shown and describedherein,'as obvious modifications and equivalents will be apparent to oneskilled in the art, and the invention is therefore to be limited only bythe scope of the appended claims.

We claim:

l. A composition of matter comprising an aqueous solution of ananti-inflammatory steroid hormone of the11,6,17,21-trihydroxypregnane-3,20-dione class and as a nonionicsurfactant solubilizing agent, polyoxyethylene sorbitan monooleate, saidcomposition having the following formula:

Water, q.s. ad. 100 percent.

wherein x represents the solubility of the anti-inflammatory steroid'hormone in water at room temperature in percent and n is from one toten, said anti-inflammatory steroid hormone being selected from theclass consisting of hydrocortisone, 2-methylene-hydrocortisone, A-hydrocortisone, G-methylhydrocortisone, 6-methyl-A -hydrocortisone,l6-hydroxy-9m-fiuorohydrocortisone, 16-hydroxy- 9a-fluoro-A-hydrocortisone, and the substantially waterinsoluble 21-esters andthesub'stantially water-insoluble 16,21-diesters thereof.

2. A composition of mattercomprising an aqueous solution containing twoto 25 percent polyoxyethylene sorbitan monooleate and 0.056 to 0.56percent hydrocortisone. 4

3. The process which comprises dissolving a polyoxyethylene sorbitanmonooleate in water and then dissolving in the solution obtained amember selected from the group of steroid hormones consisting ofhydrocortisone, Z-methylene-hydrocortisone, A -hydrocortisone,G-methylhydrocortisone, 6-methyl-A -hydrocortisone, 16-hydroxy-9a-fluorohydrocortisone, 16-hydroxy-9a-fiuoro-A -hydrocortisone, andthesubstantially water-insoluble 2l-esters and the substantiallywater-insoluble 16,21-diesters thereof, the amount of polyoxyethylenesorbitan monooleate being in the range-of from about 2 to about 25% andbeing sufiicient to increase the solubility of the steroid hormonesubstantially above that which can be dissolved in water alone, theamount of steroid hormone thus dissolved being greater than the amountwhich can be dissolved in water alone.

4. The process of claim 3 in which the solution of the steroid hormoneis heated to at least about 40 C. for at least about 15 minutes.

5. The process for preparing an aqueous solution of an anti-inflammatorysteroid hormone selected from the group consisting of hydrocortisone,Z-methyIene-hydrocortisone, A -hydrocortisone, 6-methyl-hydrocortisone,6- methyl-A -hydrocortisone, 16-hydroxy-9a-fiuorohydrocortisone,16-hydroxy-9a-fiuoro-A hydrocortisone, and the substantiallywater-insoluble 21-esters and the substantially water-insoluble16,2l-diesters thereof which comprises dissolving polyoxyethylenesorbitan monooleate in about 50 to of the required water, dissolving theanti-inflammatory steroid hormone in the solution thus prepared anddiluting the obtained solution with the remainder of the required water,the amount of polyoxyethylene sorbitan monooleate being in the range offrom about 2 to about 25 and being sufficient to increase the solubilityof the steroid hormone substantially above that which can be dissolvedin water alone and its total amount of water being insufficient in theabsence of said polyoxyethylene sorbitan monooleate to dissolve all ofthe said anti-inflammatory steroid hormone.

6. The process of claim 5 in which the solution of the anti-inflammatorysteroid hormone is heated to at least 40 C. for at least about 15minutes.

References Cited in the file of this patent UNITED STATES PATENTS2,497,509 Miescher Feb. 14, 1950 2,653,955 Rogers Sept. 29, 19532,779,707 Jacobson Jan. 29, 1957 2,779,775 Sarett Ian. 29, 1957 OTHERREFERENCES (Copy in

1. A COMPOSITION OF MATTER COMPRISING AN AQUEOUS SOLUTION OF ANANTI-INFLAMMATORY STEROID HORMONE OF THE11B,17A,21-TRIHYDROXPREGNAME-3,20-DIONE CLASS AND AS A NONOINICSURFACTANT SOLUBILIZING AGENT, POLYOXYETHYLENE SORBITAN MONOOLEATE, SAIDCOMPOSITION HAVING THE FOLLOWING FORMULA: